A very mild access to 3,4-dihydroisoquinolines using triphenyl phosphite-bromine-mediated bischler-napieralski-type cyclization

Article abstract of DOI:10.1055/s-0028-1083544

Substituted β-phenylethylamides undergo smooth intramolecular cyclization to 3,4-dihydroisoquinolines in good to excellent yields when treated with bromotriphenoxyphosphonium bromide at -60°C in dichloromethane in the presence of triethylamine. The reaction proceeds under the mildest conditions ever reported for Bischler-Napieralski-type cyclizations. When chlorotriphenoxyphosphonium choride is used, low yields are obtained instead. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083544

LETTER
2807
A Very Mild Access to 3,4-Dihydroisoquinolines Using Triphenyl Phosphite–
Bromine-Mediated Bischler–Napieralski-Type Cyclization
M
ild Bischler–Na
p
a
ieralski-T
y
n
pe Cyclizatio
i
n
to 3,
e
4-Dihydroi
l
soquin
e
olines Vaccari, Paolo Davoli, Claudia Ori, Alberto Spaggiari, Fabio Prati*
Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Fax +39(059)373543; E-mail: fabio.prati@unimore.it
Received 18 July 2008
This paper is dedicated to Albert Hofmann (1906–2008) in recognition of his pioneering work in the chemistry of mind-altering alkaloids.
best, acetonitrile, is always required. Although all these
Abstract: Substituted b-phenylethylamides undergo smooth in-
methods are operatively simple, the harsh reaction condi-
tions may result detrimental, especially when sensitive
functional groups are resident. To circumvent such limita-
tramolecular cyclization to 3,4-dihydroisoquinolines in good to ex-
cellent yields when treated with bromotriphenoxyphosphonium
bromide at –60 °C in dichloromethane in the presence of triethyl-
amine. The reaction proceeds under the mildest conditions ever re- tions, milder reaction conditions under which Bischler–
ported for Bischler–Napieralski-type cyclizations. When
Napieralski-type cyclizations can be performed have also
chlorotriphenoxyphosphonium choride is used, low yields are ob-
been developed. These include, for instance, triphos-
tained instead.
gene,15 (COCl)2/FeCl3 in dichloromethane,16 Ph3P in re-
fluxing CCl417 or, in the case of 3,4-dihydroisoquinolones,
Key words: Bischler–Napieralski cyclization, phosphonium ha-
lides, iminoyl halides, isoquinoline alkaloids, necatorone, triphenyl
phosphite
Tf2O/DMAP18 or AlCl3/KI.19
In the course of our studies on mild activation of amides
using chlorotriphenoxyphosphonium chloride, viz.
(PhO)3P+ClCl–(TPPCl2),20 indolamides were found to un-
The isoquinoline skeleton features as the structural back-
dergo efficient Bischler–Napieralski-type intramolecular
bone in a plethora of alkaloids that occur typically, though
cyclization, which allowed us to disclose a very mild and
by no means exclusively, in the plant kingdom, and which
straightforward access to 3,4-dihydro-b-carbolines in
are endowed with a most impressive array of biological
good to excellent yields.21 By contrast, when activated
and pharmacological activities.1,2
b-phenylethylamides were used, formation of the corre-
Far back in 1893, Bischler and Napieralski paved the way
sponding 3,4-dihydroisoquinolines proceeded only in
poor yields.21 Such a failure was attributed to the lower re-
activity of the phenyl ring toward electrophilic substitu-
tion compared to the indole nucleus, and we surmised that
an increase of the electrophilic character of the iminoyl
halide intermediate would result in a more efficient cy-
clization to the desired 3,4-dihydroisoquinoline frame-
work with much more satisfactory yields. As our own
results on the dehydration of aromatic and aliphatic
amides were meanwhile revealing a much higher reactiv-
ity of bromotriphenoxyphosphonium bromide, viz.
(PhO)3P+BrBr–(TPPBr2), with respect to TPPCl2,22 we felt
that the same kind of triphenyl phosphite–bromine-based
chemistry could be successfully extended to the cyclocon-
densation of b-phenylethylamides to 3,4-dihydroisoquin-
olines.
to the synthesis of isoquinoline alkaloids by succeeding in
preparing simple 3,4-dihydroisoquinolines by dehydra-
tion of b-phenylethylamides with either P2O5 or ZnCl2 at
temperatures above 250 °C.3 Ever since, this reaction,
which has been traditionally referred to as the Bischler–
Napieralski cyclization,4 has represented one of the most
general methods for the construction of isoquinoline scaf-
folds en route to the total synthesis of natural alkaloids, in
addition to the similarly useful and somewhat comple-
mentary Pictet–Spengler cyclization which, by contrast, is
usually preferred when the 1,2,3,4-tetrahydroisoquinoline
scaffold is desired instead.5
In the Bischler–Napieralski reaction, a suitable halogenat-
ing agent brings about the activation of the starting b-aryl-
ethylamide into an iminoyl chloride species which
rearranges to a nitrilium ion intermediate that subsequent-
ly undergoes intramolecular electrophilic aromatic substi-
tution.6 In general, common reagents for the reaction are
represented by POCl3,7 P2O5–POCl3,8 polyphosphoric
acid–POCl3,9 P2O5–pyridine,10 polyphosphate esters,11
phosphonitrilic chloride,12 as well as less conventional
systems such as POCl3 in ionic liquids13 or acidic zeo-
lites.14 However, heating at reflux in toluene or, at the very
To put this plan into practice, a suitable set of variously
substituted b-phenylethylamides was prepared. Amides
1a–h were synthesized in multigram scale by standard
acylation of the parent amine following well trodden
paths.23 When b-phenylethylamides 1a–h were treated
with a slight excess of freshly prepared TPPBr2 at –60 °C
in dichloromethane in the presence of triethylamine, the
cyclization products 2a–h were obtained in moderate to
excellent yields (Scheme 1).
In a typical experiment, bromine is added to a solution of
triphenyl phospite in anhydrous dichloromethane main-
tained at –60 °C under argon atmosphere. Triethylamine
SYNLETT 2008, No. 18, pp 2807–2810
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083544; Art ID: G23908ST
© Georg Thieme Verlag Stuttgart · New York
1
4
.1
1
.2
0
0
8

2808
D. Vaccari et al.
LETTER
R1
R2
R1
R2
the basidiomycete Lactarius plumbeus (Bull.: Fr.) Gray
[syn. L. turpis (Weinm.) Fr., L. necator (Bull.: Fr.) P.
Karst. ss. auct.], which has been shown to possess strong
mutagenic activity, as well as moderate antibiotic proper-
ties.26
–
[(PhO)3PBr]+ Br
HN
R4
N
CH2Cl2, –60 °C
R3
O
R3
R4
1a–h
2a–h
Mechanistically, the Bischler–Napieralski reaction is well
known to proceed through intramolecular electrophilic
aromatic substitution of an iminoyl halide intermediate
which is generated by the action of suitable phosphorus-
based halogenating agents on a N-acyl b-arylethylamine.
Once formed, the iminoyl halide species is trapped by an
electron-rich aromatic ring such as an indole or a substi-
tuted phenyl ring.6 In comparison to chlorine, bromine
acts as a better leaving group and favors the formation of
the intramolecularly tethered nitrilium ion, thus increas-
ing the reaction rate and limiting the formation of undesir-
able side products, for example, elimination of byproducts
such as nitriles and alkyl halides that may arise from von
Braun degradation which is favored by higher tempera-
tures.6b Such a mechanistic view is well corroborated by
our own set of experimental data which reveal the superi-
or performance of TPPBr2 over TPPCl2 in the cyclization
of activated as well as inactivated b-phenylethylamides to
3,4-dihydroisoquinolines.
Scheme 1 TPPBr2-promoted Bischler–Napieralski-type cyclization
of b-phenylethylamides to 3,4-dihydroisoquinolines
and the amide are then added, and the mixture is gradually
warmed to room temperature over a period of two hours,
and left to stir overnight. The resulting 3,4-dihydroiso-
quinoline is recovered as free base after acid/base extrac-
tion, and no further chromatographic purification is
required.24 The cyclization results are summarized in
Table 1.
Activated b-phenylethylamides 1c–h (entries 3–8) afford-
ed the corresponding 3,4-dihydroisoquinolines in good to
excellent yields (62–92%). Results for homoveratryl-
amides 1e–g (entries 5–7) are comparable, showing that
the effect of different N-acyl groups on the cyclization is
negligible, as already observed for Bischler–Napieralski
cyclizations under classical conditions.4b Further increase
in the ring substitution degree is likely to expose the aro-
matic ring to side reactions and may account for the slight-
ly lower yield observed for the cyclization of N-acetyl
mescaline 1h (entry 8). By contrast, in the case of amides
1a and 1b (entries 1 and 2) where the cyclization is bound
to occur either onto an inactivated phenyl ring or on ring
positions which are not activated, respectively, yields are
poor. With these inactivated substrates, TPPCl2 failed to
afford any cyclization product, and even in the case of ac-
tivated b-phenylethylamides 1e and 1h the cyclization
yields remained unsatisfactory, thereby limiting the usage
of TPPCl2 for the synthesis of 3,4-dihydroisoquinolines.
When compared to traditional Bischler–Napieralski-type
cyclizations that have been used in the literature for the
synthesis of 3,4-dihydroisoquinolines 2a–h (Table 1,
right-hand-side column), our TPPBr2-mediated protocol
features comparable to superior yields under much milder
reaction conditions, even in the case of inactivated b-phe-
nylethylamides 1a,b which classically require treatment
with harsh dehydrating agents upon prolonged heating at
temperatures of 200 °C or above.
In conclusion, the peculiar halogenating potential of triph-
enyl phosphite–bromine27 toward the activation of amides
into the corresponding iminoyl bromides at temperatures
as low as –60 °C has been conveniently employed in the
framework of a Bischler–Napieralski-type cycloconden-
sation of N-acyl b-phenylethylamines to 3,4-dihydroiso-
quinolines under the mildest conditions ever reported in
Of note, compound 2e is dehydrosalsolidine, a plant alka-
loid which occurs in the saguaro cactus Carnegiea gi-
gantea (Engelmann) Britton and Rose.1c By contrast,
isoquinoline 2g represents a synthetic precursor of neca-
torone,25 a fungal pigment isolated from fruiting bodies of
Table 1 TPPBr2-Promoted Bischler–Napieralski-Type Cyclization of N-Acyl-b-phenylethylamines to 3,4-Dihydroisoquinolinesa
Entry
Substrate R1
R2
R3
H
R4
Product
2a
Yield (%)
26 (0)b
27 (0)b
62
Lit. yields (%)
23–539,28,29
369,28,30
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
H
Me
H
OMe
H
H
Me
2b
OMe
OCH2O
OMe
OMe
OMe
OMe
H
Me
2c
52–8313,28,30
79–8631
H
Me
2d
90
OMe
OMe
OMe
OMe
H
Me
2e
80 (23)b
92
78–9610a,13,16,17,31,32
43–858a,10a,17,33
90–9325b,34
6535
H
Ph
2f
1g
H
5-MeO-2-O2NC6H3
Me
2g
89
1h
OMe
2h
73 (25)b
a Reaction conditions: amide (1.0 mmol), (PhO)3P (1.2 mmol), Br2 (1.2 mmol), Et3N (1.3 mmol), CH2Cl2 (20 mL), –60 °C to r.t.
b Yields in parentheses refer to TPPCl2-mediated reactions: –30 °C to r.t.
Synlett 2008, No. 18, 2807–2810 © Thieme Stuttgart · New York

LETTER
Mild Bischler–Napieralski-Type Cyclization to 3,4-Dihydroisoquinolines
2809
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Acknowledgment
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(24) Synthesis of 6,7-Dimethoxy-1-phenyl-3,4-dihydro-
isoquinoline (2f)
Triphenyl phosphite (0.89 mL, 3.41 mmol) was dissolved in
anhyd CH2Cl2 (20 mL) and cooled to –60 °C. Bromine (0.18
mL, 3.41 mmol) and anhyd Et3N (0.51 mL, 3.69 mmol) were
introduced sequentially under argon flow. N-[2-(3,4-dimeth-
oxyphenyl)ethyl]benzamide (1f, 819 mg, 2.84 mmol) was
then added in one portion to the bright yellow solution
maintained at the same temperature under vigorous stirring.
The resulting mixture was gradually warmed to r.t. over a
2 h period, and left to stir overnight. Subsequently, the dark
reaction mixture was extracted with 3 M HCl (3 × 15 mL),
the combined aqueous layers were basified with 10% aq
NaOH until pH = 11 and extracted with CH2Cl2 (3 × 15 mL).
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Synlett 2008, No. 18, 2807–2810 © Thieme Stuttgart · New York

2810
D. Vaccari et al.
LETTER
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The pooled organic phases were dried over MgSO4, filtered,
and evaporated under reduced pressure to afford the desired
3,4-dihydroisoquinoline 2f as a brownish liquid (692 mg,
92% yield). 1H NMR (200 MHz, CDCl3): d = 2.68 (2 H, t,
J = 7.4 Hz, CH2CH2N), 3.67 (3 H, s, OMe), 3.77 (2 H, q,
J = 7.4 Hz, CH2CH2N), 3.86 (3 H, m, OMe), 6.75 (2 H, s,
arom.), 7.36–7.59 (5 H, m, Ph). 13C NMR (50 MHz, CDCl3):
d = 26.0, 47.6, 56.0, 56.1, 110.4, 111.7, 120.0, 121.5, 128.1,
128.7, 129.2, 129.8, 132.5, 139.1, 147.5. MS: m/z = 235
[M+], 220, 204, 190, 177, 162,159, 146, 133, 110, 103, 91,
77, 65. Anal. Calcd for C12H13ClN2: C, 76.38; H, 6.41; N,
5.24. Found: C, 76.59; H, 6.65; N, 5.08.
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